tbuckley/cabot-search huggingface dataset:
Nonrotation of Bowel
Authors: ANTHONY P. YUDD, P TODD MAKLER, ARTHUR W. NOEL, ABASS ALAVI
Journal: Clinical Nuclear Medicine (1985)

When scanning for Meckel's diverticula, false-positive results have been reported due to arteriovenous malformation, tumor, intussusception, inflammation, and Gl duplication. We observed right upper quadrant accumulation due to nonrotation of the bowel, which could be an additional cause for a false-positive scan.
DrSim: Similarity Learning for Transcriptional Phenotypic Drug Discovery
Authors: Zhiting Wei, Sheng Zhu, Xiaohan Chen, Chenyu Zhu, Bin Duan, Qi Liu
Journal: Genomics Proteomics & Bioinformatics (2022)

Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as connectivity map (CMap) and library of integrated network-based cellular signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed. Among them, the fundamental issue is to define the proper similarity between transcriptional profiles. Traditionally, such similarity has been defined in an unsupervised way. However, due to the high dimensionality and the existence of high noise in high-throughput data, similarity defined in the traditional way lacks robustness and has limited performance. To this end, we present DrSim, which is a learning-based framework that automatically infers similarity rather than defining it. We evaluated DrSim on publicly available in vitro and in vivo datasets in drug annotation and repositioning. The results indicated that DrSim outperforms the existing methods. In conclusion, by learning transcriptional similarity, DrSim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and manual of DrSim are available at https://github.com/bm2-lab/DrSim/.
A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo
Authors: Jasper Fuk-Woo Chan, Yoo Jin Oh, Shuofeng Yuan, Hin Chu, Man-Lung Yeung, Daniel Canena, Chris Chung-Sing Chan, Vincent Kwok-Man Poon, Chris Chun-Yiu Chan, Anna Jinxia Zhang, Jian-Piao Cai, Zi-Wei Ye, Lei Wen, Terrence Tsz-Tai Yuen, Kenn Ka-Heng Chik, Huiping Shuai, Yixin Wang, Yuxin Hou, Cuiting Luo, Wan-Mui Chan, Zhenzhi Qin, Ko-Yung Sit, Wing-Kuk Au, Maureen Legendre, Rong Zhu, Lisa Hain, Hannah Seferovic, Robert Tampé, Kelvin Kai-Wang To, Kwok-Hung Chan, Dafydd Gareth Thomas, Miriam Klausberger, Cheng Xu, James J. Moon, Johannes Stadlmann, Josef M. Penninger, Chris Oostenbrink, Peter Hinterdorfer, Kwok-Yung Yuen, David M. Markovitz
Journal: Cell Reports Medicine (2022)

"Pan-coronavirus" antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound's broad-spectrum antiviral activity and the lack of resistant mutants.
Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022
Authors: D. Araujo, A. Greystoke, S. Bates, A. Bayle, E. Calvo, L. Castelo-Branco, J. de Bono, A. Drilon, E. Garralda, P. Ivy, O. Kholmanskikh, I. Melero, G. Pentheroudakis, J. Petrie, R. Plummer, S. Ponce, S. Postel-Vinay, L. Siu, A. Spreafico, A. Stathis, N. Steeghs, C. Yap, T.A. Yap, M. Ratain, L. Seymour
Journal: Annals of Oncology (2022)
Challenges and opportunities for precision medicine in neurodevelopmental disorders
Authors: George T. Chen, Daniel H. Geschwind
Journal: Advanced Drug Delivery Reviews (2022)

Neurodevelopmental Disorders (NDDs) encompass a broad spectrum of disorders, linked because of their origins in brain developmental processes, including diverse conditions across the age span, including autism spectrum disorders (ASD) and schizophrenia (SCZ). Clinical treatment of these disorders has traditionally focused on symptom management, as the severity of developmental disruption varies widely and the precise molecular mechanisms, timing, and progression of these disorders is usually not known. Several hundred genes have been identified as major risk factors for ASD and SCZ, which creates new potential therapeutic avenues, and there is strong evidence that these genes converge upon key molecular pathways, pointing to opportunities for precision medicine. In this review, we focus on forms of ASD and SCZ with known genetic etiologies and discuss advances in research technologies that enable a more systemic understanding of disease progression. We highlight recent advances in targeted clinical treatment and discuss ongoing preclinical efforts as well as new initiatives aimed at developing scalable platforms for NDD precision medicine.
New insights into methylome alterations and consequences during myofibroblastic differentiation in pulmonary fibrosis
Authors: Arnaud A. Mailleux, Bruno Crestani
Journal: European Respiratory Journal (2022)

Fibroblasts within the stroma play a crucial role in tissue architecture homeostasis. These mesenchymal cells are at the front line after tissue injury to support epithelial repair through their differentiation into "physiological" myofibroblasts, followed by their programmed dismissal at the end of the process [1, 2]. Chronic injuries may lead to unbalanced cell–cell communication that would promote the persistence of activated "pathological" myofibroblasts and hence excessive accumulation of extracellular matrix (ECM) components, one of the salient marks of fibrosis. In the lung, interstitial fibrosis leads to alveolar destruction and lung function decline. Idiopathic pulmonary fibrosis (IPF) is the most frequent form of interstitial lung disease, with a median overall survival time of 4.5 years. Identification of MDB2 as a critical interpreter of DNA methylation during myofibroblastic differentiation downstream of TGF-β1 signalling pathway in lung fibrosis <https://bit.ly/3BIJbCW>
Previous omicron infection may be protective against reinfection with omicron variant BA.5 for at least 5 months
Authors: Michiko Koga, Kiyoko Iwatsuki-Horimoto, Tetsuhiro Kikuchi, Seiya Yamayoshi, Yoshihiro Kawaoka, Hiroshi Yotsuyanagi
Journal: Clinical Microbiology and Infection (2022)
Is bronchopulmonary dysplasia in adult age a novel COPD endotype?
Authors: Luca Bonadies, Alberto Papi, Eugenio Baraldi
Journal: European Respiratory Journal (2022)

<b>Bronchopulmonary dysplasia is a chronic respiratory disease involving inflammation that occurs in childhood and may continue into adult age. BPD can be considered the earliest and longest lasting obstructive lung disease in humans.</b>https://bit.ly/3O8TIe0
Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial
Authors: Caicun Zhou, Dingzhi Huang, Yun Fan, Xinmin Yu, Yunpeng Liu, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Elena Poddubskaya, Umut Disel, Andrey Akopov, Mikhail Dvorkin, Wenjuan Zheng, Yiyuan Ma, Yan Wang, Songzi Li, Cunjing Yu, Gareth Rivalland
Journal: Journal of Thoracic Oncology (2022)

IntroductionThe phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses.MethodsA total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m2 every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile.ResultsAt the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1–4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified.ConclusionsTislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.
Moving the dial on identifying endotypes of asthma from early life
Authors: Lucy Perrem, Padmaja Subbarao
Journal: European Respiratory Journal (2022)

No longer recognised as a single disease entity with a "one size fits all" approach to treatment, asthma is an umbrella diagnosis spanning different endotypes and clinical phenotypes. The discovery of T2 inflammation as a driver in many asthma patients transformed our understanding of this disease and inspired the discovery of targeted biological therapies [1]. T2 inflammation is mediated by cytokines including interleukin (IL)-4, IL-5 and IL-13, which then regulate the production of measurable biomarkers including IgE, blood and sputum eosinophils, and fractional exhaled nitric oxide ( F eNO) [2]. There is a need for stable biomarkers of endotype for asthma across the lifecourse to provide earlier precision medicine approaches <https://bit.ly/3PAS19i>
Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective From the International Association for the Study of Lung Cancer Pathology Committee
Authors: Mari Mino-Kenudson, Kurt Schalper, Wendy Cooper, Sanja Dacic, Fred R. Hirsch, Deepali Jain, Fernando Lopez-Rios, Ming Sound Tsao, Yasushi Yatabe, Mary Beth Beasley, Hui Yu, Lynette M. Sholl, Elizabeth Brambilla, Teh-Ying Chou, Casey Connolly, Ignacio Wistuba, Keith M. Kerr, Sylvie Lantuejoul
Journal: Journal of Thoracic Oncology (2022)
Health Effects of Pesticide Exposure in Latin American and the Caribbean Populations: A Scoping Review
Authors: Liliana A. Zúñiga-Venegas, Carly Hyland, María Teresa Muñoz-Quezada, Lesliam Quirós-Alcalá, Mariana Butinof, Rafael Buralli, Andres Cardenas, Ricardo A. Fernandez, Claudia Foerster, Nelson Gouveia, Juan P. Gutiérrez Jara, Boris A. Lucero, María Pía Muñoz, Muriel Ramírez-Santana, Anna R. Smith, Noemi Tirado, Berna van Wendel de Joode, Gloria M. Calaf, Alexis J. Handal, Agnes Soares da Silva, Sandra Cortés, Ana M. Mora
Journal: Environmental Health Perspectives (2022)

Multiple epidemiological studies have shown that exposure to pesticides is associated with adverse health outcomes. However, the literature on pesticide-related health effects in the Latin American and the Caribbean (LAC) region, an area of intensive agricultural and residential pesticide use, is sparse. We conducted a scoping review to describe the current state of research on the health effects of pesticide exposure in LAC populations with the goal of identifying knowledge gaps and research capacity building needs.We searched PubMed and SciELO for epidemiological studies on pesticide exposure and human health in LAC populations published between January 2007 and December 2021. We identified 233 publications from 16 countries that met our inclusion criteria and grouped them by health outcome (genotoxicity, neurobehavioral outcomes, placental outcomes and teratogenicity, cancer, thyroid function, reproductive outcomes, birth outcomes and child growth, and others).Most published studies were conducted in Brazil (37%, n=88) and Mexico (20%, n=46), were cross-sectional in design (72%, n=167), and focused on farmworkers (45%, n=105) or children (21%, n=48). The most frequently studied health effects included genotoxicity (24%, n=62) and neurobehavioral outcomes (21%, n=54), and organophosphate (OP) pesticides were the most frequently examined (26%, n=81). Forty-seven percent (n=112) of the studies relied only on indirect pesticide exposure assessment methods. Exposure to OP pesticides, carbamates, or to multiple pesticide classes was consistently associated with markers of genotoxicity and adverse neurobehavioral outcomes, particularly among children and farmworkers.Our scoping review provides some evidence that exposure to pesticides may adversely impact the health of LAC populations, but methodological limitations and inconsistencies undermine the strength of the conclusions. It is critical to increase capacity building, integrate research initiatives, and conduct more rigorous epidemiological studies in the region to address these limitations, better inform public health surveillance systems, and maximize the impact of research on public policies. https://doi.org/10.1289/EHP9934.
Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors
Authors: Amin H. Nassar, Elio Adib, Sarah Abou Alaiwi, Talal El Zarif, Stefan Groha, Elie W. Akl, Pier Vitale Nuzzo, Tarek H. Mouhieddine, Tomin Perea-Chamblee, Kodi Taraszka, Habib El-Khoury, Muhieddine Labban, Christopher Fong, Kanika S. Arora, Chris Labaki, Wenxin Xu, Guru Sonpavde, Robert I. Haddad, Kent W. Mouw, Marios Giannakis, F. Stephen Hodi, Noah Zaitlen, Adam J. Schoenfeld, Nikolaus Schultz, Michael F. Berger, Laura E. MacConaill, Guruprasad Ananda, David J. Kwiatkowski, Toni K. Choueiri, Deborah Schrag, Jian Carrot-Zhang, Alexander Gusev
Journal: Cancer Cell (2022)
Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors
Authors: Jordan R. Willis, Zachary T. Berndsen, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Elise Landais, Alessia Liguori, Oleksandr Kalyuzhniy, Joel D. Allen, Sabyasachi Baboo, Oluwarotimi Omorodion, Jolene K. Diedrich, Xiaozhen Hu, Erik Georgeson, Nicole Phelps, Saman Eskandarzadeh, Bettina Groschel, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullin, Nushin B. Alavi, Samantha Falcone, Sunny Himansu, Andrea Carfi, Ian A. Wilson, John R. Yates, James C. Paulson, Max Crispin, Andrew B. Ward, William R. Schief
Journal: Immunity (2022)

Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.
Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)
Authors: Michael B Atkins, Hamzah Abu-Sbeih, Paolo A Ascierto, Michael R Bishop, Daniel S Chen, Madhav Dhodapkar, Leisha A Emens, Marc S Ernstoff, Robert L Ferris, Tim F Greten, James L Gulley, Roy S Herbst, Rachel W Humphrey, James Larkin, Kim A Margolin, Luca Mazzarella, Suresh S Ramalingam, Meredith M Regan, Brian I Rini, Mario Sznol
Journal: Journal for ImmunoTherapy of Cancer (2022)

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity—for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect.
Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses
Authors: Kah Lok Chan, Juliana Gomez, Chelisa Cardinez, Nishi Kumari, Christina E. Sparbier, Enid Y.N. Lam, Miriam M. Yeung, Sylvain Garciaz, James A. Kuzich, Doen Ming Ong, Fiona C. Brown, Yih-Chih Chan, Dane Vassiliadis, Elanor N. Wainwright, Ali Motazedian, Andrea Gillespie, Katie A. Fennell, Junyun Lai, Imran G. House, Laura Macpherson, Ching-Seng Ang, Sarah-Jane Dawson, Paul A. Beavis, Andrew H. Wei, Marian L. Burr, Mark A. Dawson
Journal: Cancer Cell (2022)
Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma
Authors: Georgia M Beasley, Michael C Brown, Norma E Farrow, Karenia Landa, Rami N Al-Rohil, Maria Angelica Selim, Aaron D Therien, Sin-Ho Jung, Junheng Gao, David Boczkowski, Eda K Holl, April K S Salama, Darell D Bigner, Matthias Gromeier, Smita K Nair
Journal: Journal for ImmunoTherapy of Cancer (2022)

We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response.
Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice
Authors: Eleonora Melzi, Jordan R. Willis, Krystal M. Ma, Ying-Cing Lin, Sven Kratochvil, Zachary T. Berndsen, Elise A. Landais, Oleksandr Kalyuzhniy, Usha Nair, John Warner, Jon M. Steichen, Anton Kalyuzhniy, Amber Le, Simone Pecetta, Manfredo Perez, Kathrin Kirsch, Stephanie R. Weldon, Samantha Falcone, Sunny Himansu, Andrea Carfi, Devin Sok, Andrew B. Ward, William R. Schief, Facundo D. Batista
Journal: Immunity (2022)

Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64. We found that high affinity of the ApexGT immunogen for PCT64-germline BCRs was necessary to specifically activate KI B cells at human physiological frequencies, recruit them to germinal centers, and select for mature bnAb mutations. Relative to protein, mRNA-encoded membrane-bound ApexGT immunization significantly increased activation and recruitment of PCT64 precursors to germinal centers and lowered their affinity threshold. We have thus developed additional models for HIV vaccine research, validated ApexGT immunogens for priming V2-apex bnAb precursors, and identified mRNA-LNP as a suitable approach to substantially improve the B cell response.
IFT-Net: Interactive Fusion Transformer Network for Quantitative Analysis of Pediatric Echocardiography
Authors: Cheng Zhao, Weiling Chen, Jing Qin, Peng Yang, Zhuo Xiang, Alejandro F. Frangi, Minsi Chen, Shumin Fan, Wei Yu, Xunyi Chen, Bei Xia, Tianfu Wang, Baiying Lei
Journal: Medical Image Analysis (2022)
TGF-β in developmental and fibrogenic EMTs
Authors: Jun Ho Lee, Joan Massagué
Journal: Seminars in Cancer Biology (2022)

TGF-β plays a prominent role as an inducer of epithelial-mesenchymal transitions (EMTs) during development and wound healing and in disease conditions such as fibrosis and cancer. During these processes EMT occurs together with changes in cell proliferation, differentiation, communication, and extracellular matrix remodeling that are orchestrated by multiple signaling inputs besides TGF-β. Chief among these inputs is RAS-MAPK signaling, which is frequently required for EMT induction by TGF-β. Recent work elucidated the molecular basis for the cooperation between the TGF-β-SMAD and RAS-MAPK pathways in the induction of EMT in embryonic, adult and carcinoma epithelial cells. These studies also provided direct mechanistic links between EMT and progenitor cell differentiation during gastrulation or intra-tumoral fibrosis during cancer metastasis. These insights illuminate the nature of TGF-β driven EMTs as part of broader processes during development, fibrogenesis and metastasis.